Stent coatings comprising hydrophilic additives

ABSTRACT

A coating for implantable medical devices and a method for fabricating thereof are disclosed. The coating includes a mixture of a hydrophobic polymer and a polymeric hydrophilic additive, wherein the hydrophobic polymer and the hydrophilic additive form a physically entangled or interpenetrating system.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 10/431,711filed 8 May 2003, which is incorporated by reference as if fully setforth, including any figures, herein.

FIELD

This invention relates to implantable medical devices such as stents.More particularly, the invention relates to materials that can be usedto coat stents.

BACKGROUND

In the field of medical technology, there is frequently a necessity toadminister drugs locally. To provide an efficacious concentration to thetreatment site, systemic administration of medication often producesadverse or toxic side effects for the patient. Local delivery is apreferred method of treatment in that smaller total levels of medicationare administered in comparison to systemic dosages, but are concentratedat a specific site. For the treatment of vascular lesions, stents can bemodified with a polymeric coating to provide local drug deliverycapabilities.

Examples of polymers that can be used to coat stents or otherimplantable devices include hydrophobic polymers, for example,poly(meth)acrylates, such as poly(n-butyl methacrylate) (PBMA) andcopolymers or terpolymers having units derived from n-butyl methacrylate(BMA). PBMA and BMA-based coatings can provide effective control of therate of release of a drug from a stent. In addition, PBMA and BMA-basedpolymers are biocompatible, have good adhesion to the underlying stentsurface, are easily processable, and possess good physical andmechanical properties such as ability to withstand elongation,compression, and shear that the stent undergoes during crimping onto thecatheter, delivery to the lesion site, and expansion.

The properties of PBMA and BMA-based stent coatings can be improved,however. For example, permeability of such coatings can be too low,particularly for drugs having higher molecular weights, leading topotentially insufficient supply of the drug to the diseased site. Anability to better regulate the rate of release through the coatings isdesired. The present invention provides such coatings.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1-3 are optical micrographs of coatings according to variousembodiments of the present invention.

FIG. 4 is a graph illustrating kinetics of in vitro release of a drugthrough one stent coating of the present invention.

SUMMARY

An implantable medical device comprising a coating is provided, thecoating includes a mixture of at least one poly(meth)acrylate and atleast one polyalkylene glycol, wherein the macromolecular chains of thepoly(meth)acrylate and the polyalkylene glycol form a physicallyentangled or interpenetrating system. Examples of the poly(meth)acrylateinclude poly(methyl methacrylate), poly(ethyl methacrylate),poly(n-propyl methacrylate), poly(iso-propyl methacrylate), poly(n-butylmethacrylate), poly(iso-butyl methacrylate), poly(tert-butylmethacrylate), poly(methyl acrylate), poly(ethyl acrylate),poly(n-propyl acrylate), poly(iso-propyl acrylate), poly(n-butylacrylate), poly(iso-butyl acrylate), and mixtures thereof. Examples ofthe polyalkylene glycol include poly(ethylene glycol), poly(ethyleneoxide), poly(propylene glycol), poly(ethylene oxide-co-propylene oxide),poly(trimethylene glycol), poly(tetramethylene glycol), and mixturesthereof.

An implantable medical device comprising a coating is provided, thecoating includes a mixture of at least one hydrophobic polymer and atleast one polymeric hydrophilic compound, wherein the macromolecularchains of the hydrophobic polymer and the hydrophilic compound form aphysically entangled or interpenetrating system. The hydrophobic polymercan include poly(meth)acrylates, vinyl polymers, polyolefins,halogenanated polymers, polymers having urethane groups, polybutyrals,nylon, silicones, polycarbonate, or polysulfone. The polymerichydrophilic compound can include polyalkylene glycols, hyaluronic acid,chondroitan sulfate, chitosan, glucosaminoglucans, dextran, dextrin,dextran sulfate, cellulose acetate, carboxymethyl cellulose,hydroxyethyl cellulose, cellulosics, polypeptides, poly(2-hydroxyethylmethacrylate), polyacrylamide, polyacrylimide, poly(ethylene amine),poly(allyl amine), poly(vinyl pyrrolidone), poly(vinyl alcohol),poly(acrylic acid), poly(methacrylic acid), acrylic acid copolymers,methacrylic acid copolymers, polyvinyl alkyl ethers, non-ionictetrafunctional block-copolymer surfactants, gelatin, collagen, albumin,chitin, heparin, elastin, fibrin, and mixtures thereof.

A medical article comprising an implantable substrate and a coating isprovided, the coating includes a bulk polymer, an additive polymer inless quantity in the coating that the bulk polymer, the additive polymerbeing entangled or interpenetrated with the bulk polymer, and a drug.

A method for fabricating a coating for an implantable medical device isprovided, the method comprises forming a coating on the device, thecoating including a mixture of at least one hydrophobic polymer and atleast one polymeric hydrophilic compound, wherein the macromolecularchains of the hydrophobic polymer and the hydrophilic compound form aphysically entangled or intertwined system.

DETAILED DESCRIPTION

A coating for an implantable medical device, such as a stent, caninclude an optional primer layer, a drug-polymer layer, and an optionaltopcoat layer. The drug-polymer layer can be applied directly onto atleast a part of the stent surface to serve as a reservoir for an activeagent or a drug which is incorporated into the drug-polymer layer. Anoptional primer layer can be applied between the stent and thedrug-polymer layer to improve the adhesion of the drug-polymer layer tothe stent. An optional topcoat layer can be applied over at least a partof the drug-polymer layer to reduce the rate of release of the drug fromthe reservoir.

The topcoat layer, if used, is the outermost layer of the stent coating.If the top-coat layer is not used, the drug-polymer layer is theoutermost layer of the stent coating. The drug-polymer and/or topcoatlayer of the stent coating can include at least one hydrophobic polymer.To regulate a rate of release of the drug from the drug-polymer layerthe hydrophobic polymer(s) can be physically mixed or blended with atleast one polymeric hydrophilic additive to form a polymer system wherethe macromolecular chains of the hydrophobic polymer and the hydrophobicadditive are physically entangled, miscible, and/or interpenetrating.This polymer system can be, in one embodiment, the outermost region orlayer of the coating.

Hereinafter, the hydrophobic polymer is also referred to as “polymer,”and polymeric hydrophilic additive is also referred to as “additive.”The term “physically entangled” is defined hereinafter as apolymer/additive composition in which neither the polymer nor theadditive forms a separate phase domain having a size larger than about100 nanometers, such as the size larger than about 200 nanometers, forexample, larger than about 300 nanometers. The size of the domain isdetermined by the largest linear dimension of the domain particle, e.g.,by the diameter of a particle in case the domain particles are spheres.The definition of “physically entangled” also includes a condition thatonce the polymer and the additive have become physically entangled, theydo not disentangle but remain physically entangled for the duration ofthe service of the coating or until the drug has been released from thecoating.

The hydrophobic polymer and the hydrophobic additive are definedhereinafter as “miscible” if the thermogram of the polymer/additivemixture shows substantially no thermal transitions attributable toeither the essentially pure polymer or the essentially pure additive.The thermogram can be obtained by a standard method of thermal analysisknown to those having ordinary skill in the art, for example, by themethod of differential scanning calorimetry.

The term “interpenetrating” is defined as the polymer/additive systemwhere the polymer and the additive form an interpenetrating polymernetwork (IPN). The definition of the IPN used by the International Unionof Pure and Applied Chemistry (IUPAC) is adopted herein. The IUPACdescribes the IPN as a polymer comprising two or more networks which areat least partially interlaced on a molecular scale, to form bothchemical and physical bonds between the networks. The networks of an IPNcannot be separated unless chemical bonds are broken. In other words, anIPN structure represents two or more polymer networks that are partiallychemically cross-linked and partially physically entangled.

To define the terms “hydrophobic” and “hydrophilic” for the purposes ofthe present invention, one of the two criteria can be used. According toone criterion, a component in the polymer/additive system (i.e., thepolymer or the additive) can be classified by the value of thecomponent's equilibrium water adsorption. Whichever component in thepolymer/additive system has the greater value of the equilibrium wateradsorption at room temperature is considered hydrophilic and the othercomponent is considered hydrophobic. If more than two components areused in the polymer/additive system, then each can be ranked in order ofits equilibrium water adsorption value. In one embodiment, the polymeris considered hydrophobic if it has an equilibrium water adsorption lessthan 10 mass % at room temperature, and the additive is consideredhydrophilic if it has an equilibrium water adsorption at roomtemperature of 10 mass % or greater.

According to another criterion, a component in the polymer/additivesystem can be classified by the value of the component's Hildebrandsolubility parameter δ. The term “Hildebrand solubility parameter”refers to a parameter measuring the cohesion of a substance and isdetermined as follows:δ=(ΔE/V)^(1/2)where δ is the solubility parameter, (cal/cm³)^(1/2);

ΔE is the energy of vaporization, cal/mole; and

V is the molar volume, cm³/mole.

Whichever component in the polymer/additive system has lower δ valuecompared to the δ value of the other component in the blend isdesignated as a hydrophobic component, and the other component withhigher δ value is designated as hydrophilic. If more than two componentsare used in the blend, then each can be ranked in order of its δ value.In one exemplary embodiment, the δ value defining the boundary betweenthe hydrophobic and hydrophilic components of the polymer/additivesystem can be about 10.7 (cal/cm³)^(1/2).

Hydrophobic substances typically have a low δ value. In one embodiment,a component in the polymer/additive system that is “hydrophobic” canhave a Hildebrand solubility parameter lower than about 10.7(cal/cm³)^(1/2). A component in the polymer/additive system that is“hydrophilic” can have a solubility parameter greater than about 10.7(cal/cm³)^(1/2).

To make the polymer/additive mixture, the polymer can be blended withthe additive and the blend can be dissolved in a solvent or in a systemcomprising a mixture of solvents. The term “dissolved” means that thepolymer/additive blend, when combined with a suitable solvent or amixture of solvents, is capable of forming a system which can be appliedon a stent by a common technique, such as spraying or dipping. Thesolvent or a mixture of solvents can be selected by those havingordinary skill in the art depending, among other factors, on the natureof the polymer and the additive.

The polymer/additive solution can be then applied on the stent by acommonly known technique known to those having ordinary skill in theart, for example, by spraying or dipping, followed by drying, forexample, by baking. The polymer/additive solution can be used to formthe topcoat layer and/or the drug-polymer layer of the stent coating.

The combined mass concentration of the polymer and the additive in thepolymer/additive solution can be between about 1% and about 10%, forexample, about 2%. A ratio between the hydrophobic polymer and thepolymeric hydrophilic additive in the polymer/additive solution can bebetween about 99:1 and about 9:1, such as between about 74:1 and about14:1, more narrowly between about 49:1 and about 19:1. For example, fora polymer/additive solution containing about 2 mass % of the hydrophobicpolymer, the concentration of the polymeric hydrophilic additive can bebetween about 0.04 and about 0.1 mass % of the total mass of thesolution.

The polymer/additive solution can be prepared by various alternativemethods. For example, the hydrophobic polymer and the polymerichydrophilic additive can be dissolved separately to obtain a hydrophobicpolymer solution and a polymeric hydrophilic additive solution, followedby combining the two solutions to form the polymer/additive solution.Alternatively, the hydrophobic polymer can be dissolved first to formthe hydrophobic polymer solution, followed by adding the polymerichydrophilic additive to the hydrophobic polymer solution to form thepolymer/additive solution. As another alternative, the additive can bedissolved first to form the additive solution followed by adding thepolymer to form the polymer/additive solution.

Examples of hydrophobic polymers include poly(meth)acrylates. The term“poly(meth)acrylates” refers to both polymethacrylates andpolyacrylates. Examples of poly(meth)acrylates that can be used includehomo-and copolymers of butyl methacrylate, for example PBMA,poly(vinylidene fluoride-co butyl methacrylate), or poly(methylmethacrylate-co-butyl methacrylate). Representative examples of otherhydrophobic polymers that can be used in practice of the presentinvention include the following polymers and mixtures thereof:

(a) poly(meth)acrylates other than PBMA or BMA-based polymethacrylates,such as poly(methyl methacrylate), poly(ethyl methacrylate),poly(n-propyl methacrylate), poly(iso-propyl methacrylate),poly(iso-butyl methacrylate), poly(tert-butyl methacrylate), poly(methylacrylate), poly(ethyl acrylate), poly(n-propyl acrylate),poly(iso-propyl acrylate), poly(n-butyl acrylate), and poly(iso-butylacrylate);

(b) vinyl polymers such as poly(ethylene-co-vinyl alcohol), for example,poly(ethylene-co-vinyl alcohol) having a molar content ofethylene-derived units of at least 44%, poly(ethylene-co-vinyl acetate),poly(vinyl acetate), polystyrene, poly(styrene-co-iso-butylene),poly(styrene-co-ethylene-co-butylene-co-styrene) terpolymers, andpoly(styrene-co-butadiene-co-styrene) terpolymers;

(c) polyolefins, for example, atactic polypropylene;

(d) halogenated (e.g., fluorinated or chlorinated) polymers such aspoly(vinyl fluoride), poly(vinylidene fluoride), polyhexafluoropropene,poly(hexafluoropropene-co-vinylidene fluoride),poly(ethylene-co-hexafluoropropene), various grades of amorphous TEFLON(including polytetrafluoroethylene) available from E.I. Du Pont deNemours & Co., poly(vinyl chloride), and poly(vinylidene chloride);

(e) polymers having urethane groups, such as polyether urethanes,polyester urethanes, polyurethaneureas, polycarbonate urethanes, andsilicone urethanes; and

(f) polybutyrals, nylon, silicones, polycarbonate, and polysulfone.

Representative examples of polymeric hydrophilic additives that can beused in practice of the present invention include hyaluronic acid,chondroitan sulfate, chitosan, glucosaminoglucans, dextran, dextrin,dextran sulfate, cellulose acetate, carboxymethyl cellulose,hydroxyethyl cellulose, cellulosics, poly(ethylene glycol)(PEG),poly(ethylene oxide), poly(propylene glycol), PLURONIC, TETRONIC,poly(trimethylene glycol), poly(tetramethylene glycol), polypeptides,poly(2-hydroxyethyl methacrylate), polyacrylamide, polyacrylimide,poly(ethylene amine), poly(allyl amine), poly(vinyl pyrrolidone),poly(vinyl alcohol), poly(acrylic acid), poly(methacrylic acid), acrylicacid copolymers, methacrylic acid copolymers, polyvinyl alkyl etherssuch as poly(vinylmethyl ether) or poly(vinylethyl ether); gelatin,collagen, albumin, chitin, heparin, elastin, fibrin and mixturesthereof. PLURONIC is a trade name of a poly(ethylene oxide-co-propyleneoxide). TETRONIC is a trade name of a family of non-ionictetrafunctional block-copolymer surfactants. PLURONIC and TETRONIC areavailable from BASF Corp. of Parsippany, N.J.

To achieve the physical entanglement of the hydrophobic polymer andpolymeric hydrophilic additive, at least one polymer and at least oneadditive can be blended together in a common solvent system thatincludes at least one very volatile solvent, followed by applying thesolution onto a stent, for example, by spraying. As used herein, “veryvolatile solvent” means a solvent that has a vapor pressure greater than30 Torr at ambient temperature. Examples of very volatile solventinclude acetone and methyl ethyl ketone. Alternatively, to physicallyentangle the hydrophobic polymer and polymeric hydrophilic additive, thepolymer and the additive can be blended in the melt, and then applied tothe stent from the melt, for example by curtain coating.

One way of forming an interpenetrating system of the hydrophobic polymerand polymeric hydrophilic additive is by blending the polymer and theadditive in a solvent, or solvent blend, in which both components aresoluble. The solution can be applied onto a stent, for example, byspraying, followed by the removal of the solvent by drying. For thepolymer and the additive which are capable of forming aninterpenetrating system, the polymers and the additive are expected tointerpenetrate while still in solution, and to remain interpenetratedupon solvent removal.

Alternatively, to form an interpenetrating system of the hydrophobicpolymer and polymeric hydrophilic additive, the polymer and additive,which can be polymerized according to two different mechanisms, can beselected. For example, the hydrophobic component can be a carbonateurethane that is polymerized by condensation reactions betweenisocyanate and hydroxyl groups, while the hydrophilic additive can bepoly(2-hydroxyethyl methacrylate) that polymerizes by a free radicalmechanism. The monomers may be dissolved in a common solvent system,applied to the stent, and then polymerized directly on the stent.

As another alternative way of forming an interpenetrating system of thehydrophobic polymer and polymeric hydrophilic additive, a high molecularweight polymer and additive can be selected, each component havingreactive or associative groups that can interact with the reactive orassociative groups of the other component. For example, such hydrophilicadditive as hydroxy terminated PEG can be blended with a high molecularweight, hydrophobic polyurethane with active isocyanate groups along thebackbone. The additive and the polymer can be blended in solution,sprayed onto a stent, followed by curing. Although sometimes the twocomponents may be not miscible, the covalent bonds between them canstill prevent phase separation.

To facilitate the formation of an entangled and/or interpenetratinghydrophobic polymer-polymeric hydrophilic additive system, the polymerand the additive can be selected in such a way that the chain lengths ofthe polymer and the additive, as determined by degree of polymerization,are such as to promote the entanglement and/or interpenetration of themacromolecules of the polymer and the additive. The term “degree ofpolymerization” refers to a number of repeating monomeric units in asingle macromolecule. The chain lengths that promote the formation of anentangled and/or interpenetrating network can be such that the contourlength of the hydrophilic additive lies in the range of between about10% and about 100% of the contour length of the hydrophobic polymer, forexample, between 50% and 100%, such as 80%. The term “contour length”refers to the combined length of all bonds along the main chain (thebackbone) of a macromolecule. The contour length can be approximated asthe degree of polymerization multiplied by the number of bonds in therepeat unit. An average bond length of about 1.4 Å can be used for thecomputation. The following example can be used to illustrate how themolecular weights of the polymer and the additive can be chosen toachieve a proper ratio between the contour lengths of the polymer andthe additive.

PBMA with a number-averaged molecular weight (M_(n)) of about 200,000,has a degree of polymerization of 1,408 and has 2 bonds in the polymerbackbone per repeat unit. Thus, a contour length of a PBMA macromoleculeis about 3,940 Å. Suitable hydrophilic additive to achieve entanglementcan be PEG having contour lengths between about 394 Å and about 3,940 Å.PEG has 3 bonds per repeat unit, so for PEG having contour lengthsbetween about 394 Å and about 3,940 Å, corresponding degree ofpolymerization is approximately between 131 and 1,313, and thecorresponding M_(n) is between about 5,780 and about 57,800.

Generally, M_(n) of the hydrophobic polymer can be between about 50,000and 1000,000 Daltons, for example, about 100,000 Daltons. The molecularweight of the hydrophilic additive can be between about 5,000 and about100,000 Daltons, for example, about 40,000 Daltons. If PBMA is used asthe hydrophobic polymer, the molecular weight of PBMA can be betweenabout 100,000 and about 300,000 Daltons, for example, about 200,000Daltons. If PEG is used as the hydrophilic additive being mixed withPBMA, the molecular weight of PEG can be between about 10,000 and about60,000 Daltons, for example, about 20,000 Daltons.

The embodiments of the present invention are described in connectionwith a stent, e.g., balloon expandable or self-expandable stents;however, other implantable medical devices can also be coated. Examplesof such implantable devices include stent-grafts, grafts (e.g., aorticgrafts), artificial heart valves, cerebrospinal fluid shunts, pacemakerelectrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, availablefrom Guidant Corp. of Santa Clara, Calif.). The underlying structure ofthe device can be of virtually any design. The device can be made of ametallic material or an alloy such as, but not limited to, cobaltchromium alloy (ELGILOY), stainless steel (316L), “MP35N,” “MP20N,”ELASTINITE (Nitinol), tantalum, nickel-titanium alloy, platinum-iridiumalloy, gold, magnesium, or combinations thereof. “MP35N” and “MP20N” aretrade names for alloys of cobalt, nickel, chromium and molybdenumavailable from Standard Press Steel Co. of Jenkintown, Pa. “MP35N”consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum.“MP20N” consists of 50% cobalt, 20% nickel, 20% chromium, and 10%molybdenum. Devices made from bioabsorbable or biostable polymers couldalso be used with the embodiments of the present invention. The deviceitself can be made in whole or in part from the disclosed polymericblends.

For the drug-polymer layer, the coating can include an active agent or adrug. The drug can include any substance capable of exerting atherapeutic or prophylactic effect for a patient. The drug may includesmall molecule drugs, peptides, proteins, oligonucleotides, and thelike. The drug could be designed, for example, to inhibit the activityof vascular smooth muscle cells. It can be directed at inhibitingabnormal or inappropriate migration and/or proliferation of smoothmuscle cells to inhibit restenosis.

Examples of drugs include antiproliferative substances such asactinomycin D, or derivatives and analogs thereof (manufactured bySigma-Aldrich of Milwaukee, Wis., or COSMEGEN available from Merck).Synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁. The active agent canalso fall under the genus of antineoplastic, anti-inflammatory,antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic,antibiotic, antiallergic and antioxidant substances. Examples of suchantineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL® byBristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere®,from Aventis S.A., Frankfurt, Germany), methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax™ (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co.,Inc., Whitehouse Station, N.J.); calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), anddonors of nitric oxide. An example of an antiallergic agent ispermirolast potassium. Other therapeutic substances or agents which maybe appropriate include alpha-interferon, genetically engineeredepithelial cells, tacrolimus, dexamethasone, and rapamycin andstructural derivatives or functional analogs thereof, such as40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUSavailable from Novartis), 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.

The molecular weight of the drug can influence the choice of themolecular weights of the polymer and the additive, as well as the ratiosbetween the polymer and the additive, since the release rate of thedrugs having higher molecular weights is expected to be slower comparedwith the release rate of the drugs with lower molecular weights. Toillustrate, when the PBMA/PEG topcoat system is used in conjunction withEVEROLIMUS (having molecular weight 958 Daltons), M_(n) of PBMA can bebetween about 90,000 Daltons and about 300,000 Daltons, for example,about 190,000 Daltons and M_(n) of PEG can be between about 6,000Daltons and about 20,000 Daltons, for example, about 18,000 Daltons, andthe mass ratio between PBMA and PEG can be between about 49:1 and about9:1, for example, about 20:1. At the same time, in the case of estradiol(having molecular weight of 272), M_(n) of PBMA can be between about150,000 Daltons and about 900,000 Daltons, for example, about 300,000Daltons and M_(n) of PEG can be between about 10,000 Daltons and about50,000 Daltons, for example, about 30,000 Daltons, and the mass ratiobetween PBMA and PEG can be between about 99:1 and about 25:1, forexample about 49:1.

Embodiments of the present invention are further illustrated by thefollowing examples.

EXAMPLE 1

A first polymer solution was prepared, the solution containing:

(a) about 5 mass % of poly(n-butyl methacrylate) (PBMA) having M_(n) ofabout 154,000; and

(b) the balance, solvent mixture of acetone and cyclohexanone, themixture having a mass ratio between acetone and cyclohexanone of about4:1.

A second polymer solution was prepared, the solution containing:

(a) about 5 mass % of poly(ethylene glycol) (PEG) having M_(n) of about18,000; and

(b) the balance, solvent mixture of acetone and cyclohexanone, themixture having a mass ratio between acetone and cyclohexanone of about4:1.

The first polymer solution was combined with the second polymer solutionto prepare a PBMA/PEG solution. The amount of the first and secondpolymer solutions were selected to obtain the PBMA/PEG solution having amass ratio between PBMA and PEG of about 49:1.

The PBMA/PEG solution was cast on a glass slide, and the solvent wasremoved by drying at room temperature followed by baking at about 80° C.for about 1 hour. As a result, an adhered polymer film was formed on theglass slide. An optical micrograph of the dry PBMA/PEG film was taken intransmitted polarized light, as shown by FIG. 1. Under such light,amorphous polymers appear dark and crystalline polymers appear bright.As seen from FIG. 1, the PBMA/PEG system appears uniformly dark showinggood miscibility of PBMA and PEG. FIG. 1 does not show that PEG forms aseparate phase.

EXAMPLE 2

A PBMA/PEG solution was prepared as described in Example 1, except themass ratio between PBMA and PEG in the PBMA/PEG solution was about 19:1.A polymer film was formed on a glass slide out of the PBMA/PEG solutionas described in Example 1. An optical micrograph of the dry PBMA/PEGfilm was taken as described in Example 1. The micrograph is shown byFIG. 2. As seen from FIG. 2, the PBMA/PEG system appears mostly uniform,with some amount of the crystalline phase formed by PEG represented bybright spots on the micrograph.

EXAMPLE 3

A PBMA/PEG solution was prepared as described in Example 1, except themass ratio between PBMA and PEG in the PBMA/PEG solution was about 10:1.A polymer film was formed on a glass slide out of the PBMA/PEG solutionas described in Example 1. An optical micrograph of the dry PBMA/PEGfilm was taken as described in Example 1. The micrograph is shown byFIG. 3. As seen from FIG. 3, the PBMA/PEG system includes visiblecrystalline areas. Compared with the film described in Example 2, thefilm shown by FIG. 3 included more substantial amount of the crystallinephase formed by PEG.

EXAMPLE 4

A first composition was prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % of poly(ethylene-co-vinyl alcohol) (EVAL); and

(b) the balance, DMAC solvent.

The first composition was applied onto the surface of a bare 18 mmVISION stent (available from Guidant Corp.) by spraying and dried toform a primer layer. A spray coater was used, having a 0.014 fan nozzlemaintained at about 60° C. with a feed pressure of about 0.2 atm (about3 psi) and an atomization pressure of about 1.3 atm ( about 20 psi).About 70 μg of the wet coating was applied. The wet coating was baked atabout 140° C. for about 2 hours, yielding a dry primer layer.

A second composition was prepared by mixing the following components:

(a) about 2.0 mass % of EVAL;

(b) about 1.6 mass % of EVEROLIMUS; and

(c) the balance, DMAC solvent.

The second composition was applied onto the dried primer layer to form adrug-polymer layer, using the same spraying technique and equipment usedfor applying the primer layer. About 300 μg of the wet coating wasapplied, followed by drying, e.g., by baking as de- scribed above. Thedry drug-polymer layer contained about 130 μg of EVEROLIMUS.

A third composition was prepared by mixing the following components:

(a) about 2 mass % of PBMA having M_(n) of about 154,000; and

(b) about 0.1 mass % of PEG having M_(n) of about 18,000; and

(c) the balance, a 1:1 by mass mixture of solvents, acetone andcyclohexanone.

The third composition was applied onto the dried drug-polymer layer, toform a topcoat layer, using the same spraying technique and equipmentused for applying the primer and the drug-polymer layers. About 200 μgof the wet coating was applied, followed by drying, e.g., by baking asdescribed above. The final amount of the dried topcoat was about 50 μg.

The kinetics of release of EVEROLIMUS in vitro was studiedchromatographically (HPLC). To study the kinetics, three stents werecoated as described above in this Example. The results of this study areillustrated by the chart shown by FIG. 4. The amount of EVEROLIMUSreleased from a stent coating having the PBMA-PEG topcoat was measured(curve 1). The average of the data obtained from the three stents wasused to plot curve 1. As a control, two identical control stents wereused, except the topcoat included only pure PBMA instead of PBMA-PEG.The control curve 2 was plotted using the average of the data obtainedfrom the two control stents. As seen from FIG. 4, the rate of release ofEVEROLIMUS through the PBMA-PEG topcoat is about twice the rate ofrelease through the PBMA topcoat.

EXAMPLE 5

A primer and drug-polymer layers can be formed on a stent as describedin Example 4, but instead of EVEROLIMUS, rapamycin can be used. Atopcoat composition can then be prepared by mixing the followingcomponents:

(a) about 2 mass % of PBMA having M_(n) of about 154,000; and

(b) about 0.05 mass % of PEG having M_(n) of about 18,000;

(c) about 0.05 mass % of poly(propylene glycol) (PPG) having M_(n) ofabout 40,000; and

(c) the balance, a 1:1 by mass mixture of solvents, acetone andcyclohexanone.

If desired, poly(tetramethylene glycol) (PTMG) can be used in thetopcoat composition instead of PPG. The M_(n) of PTMG can also be about40,000. A PPG/PTMG blend having any ratio between PPG and PTMG can alsobe optionally used instead of PPG. In this example, in the topcoatcomposition the mass ratio between PEG and PPG is 1:1. If desired, theamount of PPG or PTMG, or a mixture thereof can be up to about twiceamount of PEG. Optionally, all of the PEG in the topcoat composition canbe replaced with PPG or PTMG, or with a mixture thereof.

The topcoat composition can be applied onto the dried drug-polymerlayer, to form a topcoat layer, using the same spraying technique andequipment used for applying the primer and the drug-polymer layers.About 200 μg of the wet coating can be applied, followed by drying,e.g., by baking as described above. The final amount of the driedtopcoat can be about 50 μg.

EXAMPLE 6

A primer and drug-polymer layers can be formed on a stent as describedin Example 4. A topcoat composition can then be prepared by mixing thefollowing components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 1.9mass % of poly(hexafluoropropene-co-vinylidene fluoride) (PHFP-VDF)having M_(n) about 125,000.

(b) between about 0.04 mass % and about 0.8 mass %, for example, about0.1 mass % of F127 PLURONIC copolymer; and

(c) the balance, a mixture of solvents, the solvent mixture includingacetone and cyclohexanone in a mass ratio of about 1:1.

F127 PLURONIC is a difunctional poly(ethylene oxide)-poly(propyleneoxide)-poly(ethylene oxide) triblock copolymer terminating in primaryhydroxyl groups. F127 PLURONIC has M_(n) of about 12,600.

The topcoat composition can be applied onto the dried drug-polymerlayer, to form a topcoat layer, using the same spraying technique andequipment used for applying the primer and the drug-polymer layers.About 200 μg of the wet coating can be applied, followed by drying,e.g., by baking as described above. The final amount of the driedtopcoat can be about 50 μg.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A method of fabricating a coating for an implantable medical device,comprising forming a coating on the device, the coating including amixture of at least one hydrophobic polymer and at least one polymerichydrophilic compound, wherein the macromolecular chains of thehydrophobic polymer and the hydrophilic compound form a physicallyentangled or intertwined system.
 2. The method of claim 1, wherein thedevice is a stent.
 3. The method of claim 1, wherein the hydrophobicpolymer has a Hildebrand solubility parameter lower than about 10.7(cal/cm³)^(1/2).
 4. The method of claim 1, wherein the hydrophobicpolymer has an equilibrium water adsorption less than about 10 mass % atroom temperature.
 5. The method of claim 1, wherein the hydrophobicpolymer comprises poly(meth)acrylates, vinyl polymers, polyolefins,halogenanated polymers, polymers having urethane groups, polybutyrals,nylon, silicones, polycarbonate, or polysulfone.
 6. The method of claim5, wherein the poly(meth)acrylates are selected from a group consistingof poly(methyl methacrylate), poly(ethyl methacrylate), poly(n-propylmethacrylate), poly(iso-propyl methacrylate), poly(n-butylmethacrylate), poly(iso-butyl methacrylate), poly(tert-butylmethacrylate), poly(methyl acrylate), poly(ethyl acrylate),poly(n-propyl acrylate), poly(iso-propyl acrylate), poly(n-butylacrylate), poly(iso-butyl acrylate), and mixtures thereof.
 7. The methodof claim 5, wherein the vinyl polymers are selected from a groupconsisting of poly(ethylene-co-vinyl alcohol), poly(vinyl acetate),polystyrene, poly(styrene-co-iso-butylene),poly(styrene-co-ethylene-co-butylene-co-styrene) terpolymers,poly(styrene-co-butadiene-co-styrene) terpolymers, and mixtures thereof.8. The method of claim 5, wherein the polyolefin is atacticpolypropylene.
 9. The method of claim 5, wherein the halogenanatedpolymers are selected from a group consisting of poly(vinyl fluoride),poly(vinylidene fluoride), polyhexafluoropropene,poly(hexafluoropropene-co-vinylidene fluoride),poly(ethylene-co-hexafluoropropene), polytetrafluoroethylene, poly(vinylchloride), poly(vinylidene chloride), and mixtures thereof.
 10. Themethod of claim 5, wherein the polymers having urethane groups areselected from a group consisting of polyether urethanes, polyesterurethanes, polyurethaneureas, polycarbonate urethanes, siliconeurethanes, and mixtures thereof.
 11. The method of claim 1, wherein thepolymeric hydrophilic compound is selected from a group consisting ofpolyalkylene glycols, hyaluronic acid, chondroitan sulfate, chitosan,glucosaminoglucans, dextran, dextrin, dextran sulfate, celluloseacetate, carboxymethyl cellulose, hydroxyethyl cellulose, cellulosics,polypeptides, poly(2-hydroxyethyl methacrylate), polyacrylamide,polyacrylimide, poly(ethylene amine), poly(allyl amine), poly(vinylpyrrolidone), poly(vinyl alcohol), poly(acrylic acid), poly(methacrylicacid), acrylic acid copolymers, methacrylic acid copolymers, polyvinylalkyl ethers, non-ionic tetrafunctional block-copolymer surfactants,gelatin, collagen, albumin, chitin, heparin, elastin, fibrin, andmixtures thereof.
 12. The method of claim 11, wherein the polyalkyleneglycols are selected from a group consisting of poly(ethylene glycol),poly(ethylene oxide), poly(propylene glycol), poly(ethyleneoxide-co-propylene oxide), poly(trimethylene glycol),poly(tetramethylene glycol), and mixtures thereof.
 13. The method ofclaim 1, wherein a ratio between the hydrophobic polymer and thepolymeric hydrophilic additive is between about 99:1 and about 9:1. 14.The method of claim 1, wherein the coating additionally comprises adrug.
 15. The device of claim 14, wherein the drug is selected from agroup consisting of rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin,40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, andcombinations thereof.